4-methyl-5-imidazolone-(2)-caproic acid and esters thereof



Patented Nov. 4, 1947 4-METHYL-5-IMIDAZOLONE- (2) -CAPROIC' ACID AND,ESTERS THEREOF "Robert Duschinsky, Essex Fells, N. J assignor toHoffmann-La Roche, Inc., Roche Park, Nutley, N. J a corporation of NewJersey No Drawing. Original application April 29, 1944,

Serial No. 533,396. Divided and this application March 20, 1946, SerialNo. 655,883

4 Claims.

My invention relates to new imidazolone compounds of the generalformula:

NH CHa.C'C .CH2.(CH2)".CO O R in which n designates a low integer and Rrepresents hydrogen or lower alkyl.

This application is a division of my copending application Serial No.533,396, filed April 29, 1944 which has issued as Patent No. 2,397,250,March 26, 1946.

In general, the synthesis follows the course indicated below, wherein nis a small integer and R is hydrogen or lower alkyl.

A typical example of a compound falling within my novel class ofsubstances is one in which n is 4 and R is the ethyl radical. A methodfor preparing this specific compound is given as follows.

Eznample 4-methyl-imidazolone-2 is prepared as follows:

34 g. 4-methyl-5-imidazolone-(2)-carboxylic acid ethyl ester weredissolved in 215 cc. 0.93 N NaOI-I (1 mole) and the solution kept 68hours at 5055. After cooling is was neutralized to pH 7 by gradualaddition of 37.5 cc. 5 N HCl, which was accompanied by much carbondioxide evolution and crystallization of the reaction product. Themixture was stirred in an ice bath for 1 hour, the methylimidazolonefiltered off and washed chlorine free with some ice cold Water. Afterdrying in an oven at 60, 2. first crop of 6.6 g. was obtained. M. P.184-192".

The mother-liquor was concentrated in vacuo, while the pH, which had thetendency to increase Was adjusted to 7 by gradual addition of 7 cc. NHCl, and was finally brought to dryness. The white residue was extracted3 times with 35 cc. of boiling absolute ethanol, and once with 95 percent ethanol. The alcoholic extracts, after separation from theundissolved sodium chloride, were concentrated to dryness, thus yieldinga second crop of 8.55 g. methylimidazolone melting at about 178. Totalyield: 15.15 g. Sometimes the first crop of reaction product did notcrystallize directly, but only after partial concentration of thesolution in vacuo. The product is 4-methylimidazolone-2.

5.46 g. of the foregoing 4-methyl-imidazolone- 2 were suspended in 50cc. nitrobenzene. 11.1 g. (1.04 mole) of adipic acid ethyl esterchloride were added, and the mixture stirred well in a three-neck flaskfitted with an airtight mechanical stirrer and ascending condenser. Withcooling in an ice bath 15 g. (2 moles) anhydrous aluminum chloride wereadded, which readily went into solution, accompanied by heat evolution.Then, with continuous stirring, the temperature was raised to -65 andmaintained there for 5 hours. At that time, the evolution of H01 hadcompletely stopped.

The reaction mixture was a brown, viscous liquid. It was taken up with50 g. crushed ice and 100 cc. ether, whereupon yellowish crystalsseparated which were washed chlorine and nitrobenzene-free with waterand ether. After drying at 100 in vacuo, 7.67 g. of the reaction prodnotwere obtained. M. P. 170 (unsharp). By recrystallization in cc. of 50percent ethanol, with addition of norite, 6.73 g. yellowish crystals, M.P. 171.5-173", were obtained.

The substance is soluble in alcohol and acetic acid, insoluble in waterand ether. It gives only a Very slight orange coloration with ferricchloride. The product is 4-methyl-5-imidazo1one- (2) -e-keto-caproicacid ethyl ester.

5.08 g. of this keto ester, dissolved in 50 cc. acetic acid, werehydrogenated at ordinary pressure with 2 g. prehydrogenated Adamsplatinum catalyst. In 30 minutes 977 cc. hydrogen were taken up (theory:for two moles of hydrogen 975 cc. at 24). The catalyst was filtered off,the solution concentrated in vacuo, the residue was taken up in alcohol,andthen again concentrated. The crystalline residue was finally taken upin 10 cc. alcohol, and the mixture cooled in a dry ice bath. The whitecrystals were filtered, washed with cold ethanol and ether. Yield: 3.36g. M. P. 194-196. mg. were recrystallized from 1.5 cc. ethanol and gave70 mg. material of the same melting point The substance is fairlysoluble in alcohol and acetic acid, little soluble in ether.

This final product is 4-methyl-5-imidazolone- (2)-caproic acid ethylester. The ester may be hydrolyzed in the usual manner to thecorresponding acid.

It will be understood in the descriptive portion of the specificationand in the claims that the term imidazolone, as well as the structuralrepresentation will embrace all tautomeric forms.

I claim:

1. Compounds of the general formula:

CHa.C

